Bavdegalutamide (ARV-110) Shows Promise as AR Degrader in Preclinical Prostate Cancer Models
核心洞察
Bavdegalutamide (ARV-110), a PROTAC androgen receptor degrader, demonstrates potent activity against wild-type and mutant AR (搜索) in preclinical models.
The drug exhibits superior efficacy compared to enzalutamide in reducing PSA synthesis, inhibiting cell proliferation, and inducing apoptosis in prostate cancer (搜索) cells.
Bavdegalutamide shows significant tumor growth inhibition in enzalutamide- and abiraterone-resistant prostate cancer (搜索) animal models, both as a monotherapy and in combination with abiraterone.
Androgen receptor (AR (搜索)) signaling remains a primary driver of prostate cancer (搜索) progression, even with the use of AR-targeting drugs like abiraterone and enzalutamide. Resistance often develops through AR alterations such as mutation, amplification, and splicing. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC) protein degrader designed to address this resistance by inducing the degradation of AR.
Preclinical Efficacy
Bavdegalutamide works by recruiting the cereblon-containing E3 ubiquitin ligase to ubiquitinate AR (搜索), leading to its proteasomal degradation. Preclinical studies demonstrate that bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. In cell-based assays, bavdegalutamide showed higher activity than the AR antagonist enzalutamide in suppressing prostate-specific antigen (PSA) synthesis, inhibiting prostate cancer (搜索) cell proliferation, and inducing apoptosis.
Superior Tumor Growth Inhibition
In an AR (搜索)-expressing patient-derived xenograft mouse model, bavdegalutamide significantly degraded AR and inhibited tumor growth more effectively than enzalutamide. Notably, bavdegalutamide also demonstrated robust tumor growth inhibition in animal models of enzalutamide- and abiraterone-resistant prostate cancer (搜索). Furthermore, combining bavdegalutamide with abiraterone enhanced its activity.
Clinical Development
These promising preclinical results led to the clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer (搜索). Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials and is currently being evaluated in a phase 1/2 study (NCT03888612) in patients with metastatic castration-resistant prostate cancer (mCRPC).